Substituted 3-(2-pyridinyl)-4(1H)-quinolinone N-oxides

ABSTRACT

Substituted 3-(2-pyridinyl)-4-(1H)-quinolinone N-oxides having the formula I: ##STR1## wherein R 1  is hydrogen, halogen, lower alkyl, hydroxy or alkoxy; R 2  is hydrogen or lower alkyl; R 3  is hydrogen or --CH 2  OH; the dotted line indicates the possible presence of a double bond at the 2,3-position of the quinoline ring; the pharmaceutically acceptable acid addition salts thereof; and a process for the preparation thereof, are described. The compounds of the invention are useful for the treatment of hyperacidity and for the prevention of allergic and asthmatic reactions.

DESCRIPTION OF THE PRIOR ART

Osborne et al., in J. Heterocyclic Chem. 1: 138-140 (1964), describe thepreparation of 1-phenyl-2-(2-pyridinyl)ethanone N-oxide by the acylationof 2-picoline N-oxide, using sodium amide in liquid ammonia as thecondensing agent. No pharmacological activity is reported for this orrelated compounds described by Osborne et al.

DESCRIPTION OF THE PARTICULAR EMBODIMENTS

This invention relates to substituted 3-(2-pyridinyl)-4(1H)-quinolinoneN-oxides having the formula I: ##STR2## wherein R₁ is hydrogen, halogen,lower alkyl, hydroxy or alkoxy; R₂ is hydrogen or lower alkyl; R₃ ishydrogen or --CH₂ OH; the dotted line indicates the possible presence ofa double bond at the 2,3-position of the quinoline ring; and thepharmaceutically acceptable, acid addition salts thereof. Compounds ofthe formula I above wherein R₁ is hydrogen or halogen; R₂ is hydrogen ormethyl; and R₃ is hydrogen or hydroxymethyl, as well as theirpharmaceutically acceptable, acid addition salts, are particularlypreferred.

The compounds of the invention having the formula II: ##STR3## whereinR₁ is hydrogen, halogen, lower alkyl, hydroxy or alkoxy; are prepared byreacting a compound of the formula III: ##STR4## wherein R₁ is definedabove in compound II, with a trialkylorthoformate, typicallytriethylorthoformate. The reaction is conducted in a suitable solventsuch as pyridine and the like, in the presence of an organic base,typically piperidine or pyrrolidine.

The compounds of the invention having the formula IV: ##STR5## whereinR₁ is hydrogen, halogen, lower alkyl, hydroxy or alkoxy; R₂ ' is loweralkyl; and R₃ is hydrogen or hydroxymethyl; are prepared by reacting acompound having the formula V: wherein R₁ and R₂ ' are as defined abovein compound IV, with either one or two moles of formaldehyde. If onemole of formaldehyde is used, one obtains a final product wherein R₁ andR₂ ' are as defined above in compound IV, and R₃ is hydrogen. If twomoles of formaldehyde are used, one obtains a final product wherein R₁and R₂ ' are as defined above in compound IV and R₃ is hydroxymethyl.The reaction is conducted in a suitable solvent, such as methanol andthe like, in the presence of an organic base, typically piperidine orpyrrolidine.

The starting materials III and V used in preparing the compounds of thisinvention are prepared as described in co-pending U.S. Ser. No. 611,282,filed Sept. 8, 1975. Thus, compounds of the formula III and V areprepared by reacting an N-substituted isatoic anhydride having theformula VI: ##STR6## wherein R₁ is as defined above in compounds III andV and R₄ is hydrogen or lower alkyl, with a 2-picoline N-oxide of theformula VII: ##STR7## The above reaction is conducted in liquid ammoniain the presence of an alkali metal amide condensing agent such assodium, potassium or lithium amide (sodium amide preferred).

Representative starting materials having the formulas III and V whichmay be prepared by the above-described reaction include:1-[2-aminophenyl]-2-(2-pyridinyl)ethanone N-oxide,1-[5-chloro-2(methylamino)phenyl]-2-(2-pyridinyl)ethanone N-oxide,1-[5-methoxy-2-(methylamino)phenyl]-2-(2-pyridinyl)ethanone N-oxide,1-[4-chloro-2-aminophenyl]-2-(2-pyridinyl)ethanone N-oxide,1-[5-hydroxy-2-aminophenyl]-2-(2-pyridinyl)ethanone N-oxide,1-[5-methyl-2-aminophenyl]-2-(2-pyridinyl)ethanone N-oxide, and1-[3-methoxy-2-aminophenyl]-2-(2-pyridinyl)ethanone N-oxide.

Pharmaceutically acceptable acid addition salts of the compounds of thisinvention are prepared according to conventional procedures by treatingthe free base form of the compounds of the invention in an alcoholsolution with the desired acid.

In the above formulas for the compounds of the invention, the R groupdefinitions may be more fully described as follows: the term "loweralkyl" is meant to include lower aliphatic hydrocarbons having 1 to 7,preferably 1 to 4 carbon atoms in the alkyl chain, such as methyl,ethyl, propyl, isopropyl, butyl or isobutyl. This definition for loweralkyl also applies to the alkyl portions of "alkoxy". The term "halogen"is meant to include bromine, chlorine, iodine and fluorine.

The compounds of the invention having formula II: ##STR8## wherein R₁ ishydrogen, halogen, lower alkyl, hydroxy or alkoxy, exhibitgastric/anti-secretory activity when tested according to the proceduredescribed by H. Shay et al., Gastroenterology 5: 43 (1945). In thislast-mentioned test, male Long Evans Hooded rats (150-200 gms.) arefasted for 24 hours prior to testing (water ad lib). Rats are randomlydivided into groups of 5 rats each and housed individually. At the timeof testing, each rat is lightly anesthetised with ether, its stomachexposed through a midline abdominal incision and the pylorus ligatedwith silk thread. The incision is sutured, closed and covered withFlexible Collodion, U.S.P. to prevent ingestion of blood. Test compoundor vehicle control is administered (a) intraduodenally prior to closingthe incision; (b) intraperitoneally immediately after ligation; or (c)orally as a one hour pretreatment. Four hours later, the rats aresacrificed by ether and their stomachs removed and opened.

Gastric contents are placed in centrifuge tubes and centrifuged toremove debree. The volume of gastric juice is measured (expressed inmilliliters) and titratable acidity determined electrometrically to pH7.4 (expressed as milliequivalents of acid per liter). Results areexpressed as percent reduction of volume and/or titratable acidity fromcontrol group average. Reduced gastric acid secretion in experimentalanimals in the above-described test is considered to be representativeof pharmacological utility in the treatment of hyperacidity in humans.

Thus, the compounds of the invention are active in the treatment ofhyperacidic conditions when administered to mammals at a dose level offrom about 20 to about 50 mg/kg of body weight by the oral or parenteralroute. This dosage may be varied depending on the severity of thecondition, the age, weight, sex and class of mammal being treated, aswell as the route of administration. For example, when3-(2-pyridinyl)-4(1H)-quinolinone N-oxide (the compound of Example 1) istested in the pylorus ligated rat in the above-described procedure at adose of about 20 mg/kg, intraperitoneally, a reduction of about 55.2% involume of gastric acid was obtained, compared to controls.

The compounds of the invention having formula IV: ##STR9## wherein R₁ ishydrogen, halogen, lower alkyl, hydroxy or alkoxy; R₂ ' is lower alkyland R₃ is hydrogen or hydroxymethyl, are active in prevention ofallergic conditions (typically, asthmatic reactions) in mammals such asrats and guinea pigs as evidenced by positive results in the passivecutaneous anaphylaxis screen (PCA test). The PCA screen is amodification of the procedures described by I. Mota, Life Sciences, Vol.4, No. 7: 465-474 (1963) and Z. Ovary and O. Bier, Proc. Soc. Exptl.Biol. Med., 81: 584-586 (1952) and provides a measure of theeffectiveness of test compounds in inhibiting the release or action oftoxic products arising from the combination of reaginic antibodies withspecific antigens. These toxic products are causative factors in suchdisorders as bronchial allergic asthma (extrinsic reagins), exerciseasthma, cold asthma, hay fever, perennial allergic rhinitis, foodallergies, serum or drug allergies, insect sting allergies,angioneurotic edema, atopic dermatitis, including infantile eczema,urticaria, dermographism, dermatoconjunctivitis, acute allergicconjunctivitis, chronic allergic conjunctivitis and the like.

Inhibition of reaginic antigen/antibody reactions in experimentalanimals such as rats and guinea pigs is regarded as representative ofinhibition of human reaginic antigen/antibody reactions which occurduring allergic episodes.

In the PCA screen, rats are sensitized with 1 mg of ovalbumin (Pentex,Kankakee, Ill.) intramuscularly and with 10¹⁰ B. pertussis organisms(Parke-Davis and Co., Detroit, Michigan; Bio. 210) intraperitoneally. Onthe 14th day the animals are bled and the serum prepared in the usualmanner. The reaginic nature of antiovalbumin serum thus obtained isverified by the use of standard criteria.

Passive cutaneous anaphylaxis is induced as described by Ovary and Bier(1952) and by Mota (1963). Suitable antibody concentration in 0.1 ml toresult in reactions between 7 and 19 mm in diameter (usually 1:5 to 1:40dilutions) are injected intradermally on either side of the dorsalmidline of rats. Forty-eight hours later, the animals are dosed withdrug and injected in the tail vein with 1 ml of saline containing 0.25%Evans blue and 1 mg ovalbumin. Thirty minutes later animals aresacrificed with ether, the dorsal skin reflected, and the meanorthogonal diameter of the reaction site measured.

A linear relationship can be shown to exist between the relativeantibody concentration and the diameter of the resultant reaction if theantibody concentration is adjusted to yield diameters betweenapproximately 7 and 19 mm. For each experiment, a line is fitted by theleast squares method for the relationship of the diameter to therelative antibody concentration to derive the base-line diameter. Thepercentage inhibition due to drug treatment is then calculated by theformula: ##EQU1## The significance of the inhibition is measured byStudent's t-test.

For administration, the compounds are suspended by trituration in 1% gumtragacanth and 0.15M saline so as to give 10 ml/kg body weight.

Thus, the compounds of this invention are active for the inhibition ofreagin-mediated allergic disorders when administered to mammals in needthereof at dose levels of from about 10 to about 25 mg/kg of bodyweight, by the oral or parenteral route. This dosage may be varieddepending upon the severity of the condition, the age, weight, sex andclass of mammal being treated, as well as the route of administration.For example,2,3-dihydro-3-(hydroxymethyl)-1-methyl-3-(2-pyridinyl)-4(1H)-quinolinoneN-oxide (the compound of Example 2) shows a 54% inhibition of theallergic response at 25 mg/kg when tested in a passive cutaneousanaphalaxis (PCA) screen, as described above. Consequently, thecompounds of this invention are potentially useful in the treatment ofasthma, hay fever and other allergic conditions.

In use, the compound of the invention may be combined with parenterallyacceptable vehicles, such as gum tragacanth, in saline suspension, toprovide dosage forms suitable for parenteral administration; or they maybe combined with pharmaceutical diluents such as lactose, cornstarch,and the like and formulated into tablet or capsule dosage forms.

To further illustrate the practice of this invention, the followingexamples are included.

EXAMPLE 1 ##STR10## 3-(2-Pyridinyl)-4(1H)-Quinolinone N-oxide

A solution of 1-[2-aminophenyl]-2-(2-pyridinyl)ethanone N-oxide (2.0 g),triethyl orthoformate (2.5 ml), pyridine (20 ml) and piperidine (15drops) is refluxed under nitrogen for 20 hours. The product precipitatesout. Recrystallization from N,N-dimethylformamide gives white crystals(0.9 g, 43%), m.p. dec 300° C.

Mass Spectrum

observed molecular ion: 238.sup.. 0788

calculated for C₁₄ H₁₀ N₂ O₂ 238.sup.. 0742

EXAMPLE 2 ##STR11##6-Chloro-2,3-Dihydro-1-Methyl-3-(2-Pyridinyl)-4(1H)-Quinolinone N-Oxide

A solution of 1-[5-chloro-2-(methylamino)phenyl]-2-(2-pyridinyl)ethanoneN-oxide (15 g), 36% formaldehyde (0.9 m, 4.1 g), methanol (200 ml) andpyrrolidine (2 ml) is refluxed under nitrogen for 20 minutes. Thesolvents are removed under reduced pressure. Crystallized fromisopropanol. Recrystallization from absolute ethanol gives brightyellow-green crystals (7.75 g, 49.5%), m.p. 135-37° C.

Anal. Calcd. for C₁₅ H₁₃ ClN₂ O₂ : C, 62.40; H, 4.54; N, 9.70; Cl,12.28. Found: C, 62.28; H, 4.62; N, 9.67; Cl, 12.19.

EXAMPLE 3 ##STR12##2,3-Dihydro-1-Methyl-3-(2-Pyridinyl)-4(1H)-Quinolinone N-Oxide

A solution of 1-[2-(methylamino)phenyl]-2-(2-pyridinyl)ethanone N-oxide(16.0 g), 36% formaldehyde (0.9 m, 4.96 g), methanol (100 ml) andpyrrolidine (4 ml) is refluxed under nitrogen for 50 minutes. Thesolvents are removed under reduced pressure. Crystallization fromisopropanol gives yellow-green crystals (10.45 g, 62.2%), m.p. 132-34°C.

Anal. Calcd. for C₁₅ H₁₄ N₂ O₂ : C, 70.85; H, 5.55; N, 11.02. Found: C,70.67; H, 5.63; N, 11.02.

EXAMPLE 4 ##STR13##2,3-Dihydro-3-(Hydroxymethyl)-1-Methyl-3-(2-Pyridinyl)-4(1H)-QuinolinoneN-Oxide

A solution of 1-[2-(methylamino)phenyl]-2-(2-pyridinyl)ethanone N-oxide(15.0 g), 36% formaldehyde (41.0 g), methanol (150 ml) and pyrrolidine(2 ml) is refluxed under nitrogen for 30 hours. The product crystallizedon cooling. Recrystallization from absolute ethanol gives green-yellowcrystals (8.5 g, 50%), m.p. 198-200° C.

Anal. Calcd. for C₁₆ H₁₆ N₂ O₃ : C, 67.59; H, 5.67; N, 9.85. Found: C,67.58; H, 5.69; N, 9.84.

We claim:
 1. A compound of the formula IV: ##STR14## wherein R₁ ishydrogen, halogen, 1 to 7 carbon lower alkyl, hydroxy or 1 to 7 carbonlower alkoxy; R₂ is 1 to 7 lower alkyl; R₃ is hydrogen or hydroxymethyl;and the pharmaceutically acceptable acid addition salts thereof.
 2. Acompound of the formula IV according to claim 1 wherein R₁ is hydrogenor halogen; R₂ is methyl and R₃ is hydrogen or hydroxymethyl.
 3. Acompound according to claim 1 which is6-chloro-2,3-dihydro-1-methyl-3-(2-pyridinyl)-4(1H)-quinolinone N-oxide.4. A compound according to claim 1 which is2,3-dihydro-3-(hydroxymethyl)-1-methyl-3-(2-pyridinyl)-4(1H)-quinolinoneN-oxide.
 5. A compound according to claim 1 which is2,3-dihydro-1-methyl-3-(2-pyridinyl)-4(1H)-quinolinone N-oxide.
 6. Aprocess for preparing a compound having the formula IV: ##STR15##wherein R₁ is hydrogen, halogen, 1 to 7 carbon lower alkyl, hydroxy or 1to 7 carbon lower alkoxy; R₂ is 1 to 7 carbon lower alkyl and R₃ ishydrogen or hydroxymethyl which comprises reacting a compound of theformula V: ##STR16## wherein R₁ and R₂ ' are as defined above incompound IV with formaldehyde to effect ring closure, said compound Vand formaldehyde being present in a mole ration of 1 to 1 to obtain thecompound of formula IV wherein R₃ is hydrogen; and said formaldehydebeing present in excess to obtain the compound of formula IV wherein R₃is hydroxymethyl.
 7. A process according to claim 6 wherein 1 mole ofcompound V is reacted with 1 mole of formaldehyde to obtain a compoundhaving the formula IV wherein R₃ is hydrogen.
 8. A process according toclaim 6 wherein 1 mole of compound V is reacted with 2 moles offormaldehyde to obtain a compound having the formula IV wherein R₃ ishydroxymethyl.